This invention relates to novel compounds useful in therapy, particularly in the treatment of benign prostatic hyperplasia.
International Patent Application WO 89/05297 discloses a number of substituted quinazoline compounds that are indicated as inhibitors of gastric acid secretion.
According to the present invention, there is provided a compound of formula I, 
wherein
R1 represents C1-4 alkoxy optionally substituted by one or more fluorine atoms;
R2 represents an aryl group or a heteroaryl group, optionally substituted by C1-4 alkyl or SO2NH2;
R3 represents a 4-, 5-, 6-, or 7-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring being optionally fused to a benzene ring or a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from N, O and S, the ring system as a whole being optionally substituted by one or more groups independently selected from OH, C1-4 alkyl, C1-4 alkoxy, halogen and NHSO2(C1-4 alkyl), and when S is a member of the ring system, it may be substituted by one or two oxygen atoms;
X represents CH or N; and
L is absent,
or represents a cyclic group of formula Ia, 
in which A is attached to R3;
A represents CO or SO2;
Z represents CH or N;
m represents 1 or 2, and in addition, when Z represents CH, it may represent 0; and
n represents 1, 2 or 3, provided that the sum of m and n is 2, 3, 4 or 5;
or represents a chain of formula Ib, 
in which A is attached to R3;
A and Z are as defined above;
R4 and R5 independently represent H or C1-4 alkyl; and
p represents 1, 2 or 3, and in addition, when Z represents CH, it may represent 0;
or a pharmaceutically acceptable salt thereof (referred to together herein as xe2x80x9cthe compounds of the inventionxe2x80x9d).
Pharmaceutically acceptable salts include acid addition salts, such as hydrochloride and hydrobromide salts, and phosphate salts.
Alkyl or alkoxy groups that R1-5 may represent or include can be straight chain, branched chain, cyclic, or a combination thereof.
xe2x80x9cArylxe2x80x9d in the definition of R2 means an aromatic hydrocarbon, for example phenyl or naphthyl. xe2x80x9cHeteroarylxe2x80x9d in the definition of R2 means an aromatic heterocycle, for example one having 5 or 6 ring members, at least one of which is N, O or S, such as pyridinyl or furanyl.
Preferably, heterocyclic rings represented or comprised by R3 are saturated. Examples include morpholine, thiomorpholine-1,1-dioxide, 1,4-dioxan, tetrahydrofuran and piperidine.
The compounds of the invention may be optically active. The invention includes all optical isomers of the compounds of formula I, and all diastereoisomers thereof.
The compounds of the invention may exist in a number of tautomeric forms. The invention includes all such tautomeric forms.
Preferred groups of compounds that may be mentioned include those in which:
(a) R1 represents methoxy;
(b) R2 represents phenyl or 2-pyridinyl;
(c) R3 represents morpholinyl, or a piperidine ring which is fused to a benzene or pyridine ring;
(d) L is absent or represents 1,4-diazepanylcarbonyl 
xe2x80x83and
(e) L is absent and R3 represents a piperidine ring fused to a benzene ring which is substituted by NHSO2(C1-4 alkyl).
According to the invention, there is also provided a process for the production of a compound of the invention, which comprises:
(a) when X represents CH, cyclizing a compound of formula II, 
xe2x80x83in which R1-3 and L are as defined above;
(b) when Z represents N, reacting a compound of formula IIIa or IIIb, as appropriate. 
xe2x80x83in which R1, R2, R4, R5, X, m, n and p are as defined above, with a compound of formula IV,
Lg-A-R3xe2x80x83xe2x80x83IV
xe2x80x83in which R3 is as defined above, A represents CO or SO2 and Lg represents a leaving group;
(c) reacting a compound of formula V, 
xe2x80x83in which R1, R3, X and L are as defined above, and Lg is a leaving group, with a compound of formula VI,
R2-Mxe2x80x83xe2x80x83VI
xe2x80x83in which R2 is as defined above and M represents substituted boron, zinc or tin, in the presence of a palladium catalyst;
(d) when X represents N, reacting a compound of formula VII, 
xe2x80x83in which R1 and R2 are as defined above, with a compound of formula VIIIa, VIIIb or VIIIc, as appropriate, 
xe2x80x83in which R3-5, A, Z, m, n and p are as defined above; and R3a has the same significance as R3 above except that it contains a nucleophilic nitrogen atom in the heterocyclic ring which is attached to the H in formula VIIIc;
(e) when A represents CO and R3 comprises a nucleophilic nitrogen atom in the heterocyclic ring attached to L, reacting a compound of formula IXa or IXb, as appropriate. 
in which R1, R2, R4, R5, X, Z, m, n and p are as defined above, and Lg is a leaving group, with a compound of formula VIIIc, as defined above; or
(f) conversion of a compound of formula I in which L represents a cyclic group of formula Ia, to a corresponding compound of formula I in which L represents a chain of formula Ib in which R4 and R5 each represent H, by the action of a strong base;
and where desired or necessary converting the resulting compound of formula I into a pharmaceutically acceptable salt or vice versa.
In process (a), the cyclization may be carried out in the presence of a strong base (for example lithium diisopropylamide) in a solvent that does not adversely affect the reaction (for example tetrahydrofuran), around room temperature. Alternatively, it may be performed using potassium hydroxide in a solvent which does not adversely affect the reaction (for example dimethylsulphoxide), at the reflux temperature of the solvent.
In process (b), suitable leaving groups are OH and Cl. When the compound of formula IV is a carboxylic acid, the reaction may be carried out in the presence of conventional coupling agents [for example 1-hydroxybenzotriazole monohydrate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 4-methylmorpholine] in a solvent which does not adversely affect the reaction (for example CH2Cl2) at or around room temperature. When the leaving group is Cl, the reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2 or tetrahydrofuran), around 0xc2x0 C. or up to the reflux temperature of the solvent.
In process (c), suitable leaving groups include the trifluoromethylsulphonate (triflate) group. The palladium catalyst may be tetrakis(triphenylphosphine)palladium(0). M may be B(OH)2, B(CH2CH2)2, Sn(CH2CH2CH2CH3)3, Sn(CH3)3 or ZnCl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example, when M is B(OH)2, a mixture of toluene, ethanol and 1M aqueous sodium carbonate) at an elevated temperature (for example the reflux temperature of the solvent).
In process (d), the reaction may be carried out in a solvent which does not adversely affect the reaction (for example n-butanol) in the presence of a base (for example triethylamine) at an elevated temperature (for example 100xc2x0 C.).
In process (e), suitable leaving groups include Cl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF) in the presence of a base (for example triethylamine) at room temperature.
The reaction may also be carried out without isolating the compound of formula IXa or IXb, by reacting a compound of formula IIIa or IIIb with triphosgene and a compound of formula VIIIc. In this case the leaving group is xe2x80x94Cl. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example CH2Cl2) in the presence of a base (for example triethylamine) at or around room temperature.
In process (f), suitable strong bases include lithium diisopropylamide. The reaction may be carried out in a solvent that does not adversely affect the reaction (for example THF).
Compounds of formula II [see process (a)] may be prepared by reaction of a compound of formula X, 
in which R1, R3 and L are as defined above and Lg is a leaving group (such as a triflate group), with a compound of formula VI, as defined above, using the conditions described for process (c) above.
Compounds of formula X may be prepared by converting the OH group in a compound of formula XI. 
in which R1, R3 and L are as defined above, into a leaving group (such as a triflate), for example by reaction with triflic anhydride. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2) in the presence of pyridine, below room temperature (for example xe2x88x9220xc2x0 C.).
Compounds of formula XI may be prepared by deprotecting a compound of formula XII, 
in which R1, R3 and L are as defined above and Pg is a hydroxy protecting group (such as benzyl). When Pg is benzyl, the deprotection may be achieved by hydrogenation over palladium-on-charcoal, in ethanol, around room temperature.
Compounds of formula XII may be prepared by reaction of a compound of formula XIII, 
in which R1 and Pg are as defined above, with a combination of a compound of formula XIV, 
in which R3 and L are as defined above, and phosphorous oxychloride in dichloromethane at the reflux temperature of the solvent.
Compounds of formula IIIa or IIIb [see process (b)] in which X represents CH may be prepared from compounds of formula XVa or XVb, as appropriate, 
in which R1, R2, R4, R5, m, n and p are as defined above, by bubbling HCl gas through a solution of the compound in dichloromethane.
Compounds of formula XVa or XVb may be prepared from compounds of formula XVIa or XVIb, as appropriate, 
in which R1, R2, R4, R5, m, n and p are as defined above, by cyclization using potassium hydroxide or lithium diisopropylamide at an elevated temperature (such as 90xc2x0 C.) in DMSO, quenching with water.
Compounds of formula XVIa or XVIb may be prepared from compounds of formula XVIIa or XVIIb, as appropriate, 
in which R1, R4, R5, m, n and p are as defined above, and Pg is a hydroxy protecting group, by reaction with a compound of formula VI, as defined above, using the conditions described for process (c) above.
Compounds of formula XVIIa or XVIIb may be prepared by reacting a compound of formula XIII, as defined above, with a compound of formula XVIIIa or XVIIIb, as appropriate, 
in which R4, R5, m, n and p are as defined above, by the method described above for producing compounds of formula XII.
Compounds of formula IIIa or IIIb [(see process (b)] in which X represents N may be prepared by reacting a compound of formula VII, as defined above, with a compound of formula XIXa or XIXb, as appropriate, 
in which R4, R5, m, n and p are as defined above, using the conditions mentioned for process (d) above.
Compounds of formula VII may be prepared by conventional means from known compounds (or compounds available using known techniques) according to Scheme 1 below (see also Example 1), in which R1, R2 and M are as defined above: 
Compounds of formula V [see process (c)] in which X represents CH may be prepared by cyclization of a compound of formula X, as defined above, using the reaction conditions mentioned in process (a) above.
Compounds of formula V in which X represents N may be prepared by converting the OH group in a compound of formula XX, 
in which R1, R3 and L are as defined above, into a leaving group (such as a triflate group), for example by reaction with triflic anhydride.
Compounds of formula XX may be prepared from compounds of formula XXI, 
in which R1 and Pg are as defined above, by reaction with a compound of formula VIIIa, VIIIb or VIIIc, as defined above, as appropriate, using the conditions described in process (d).
Compounds of formula XXI may be prepared from compounds of formula XIII, as defined above, by conventional means according to Scheme 2 below (see also Example 11) in which R1 and Pg are as defined above: 
The preparation of compounds of formula VII [see process (d)] has already been described above.
Compounds of formula VIIIa and VIIIb may be prepared by reaction of a compound of formula IV, as defined above, with a compound of formula XIXa or XIXb, as defined above, as appropriate, using the conditions indicated for process (d) above.
Compounds of formula IXa and IXb [see process (e)] in which Lg represents Cl may be prepared from compounds of formula IIIa or IIIb, as defined above, as appropriate, by reaction with triphosgene. The reaction may be carried out in a solvent which does not adversely affect the reaction (for example CH2Cl2) in the presence of a base (for example triethylamine) at around xe2x88x9210xc2x0 C.
Compounds of formulae IV, VI, VIIIc, XIII, XIV, XVIIIa, XVIIIb, XIXa and XIXb are either known or are available using known techniques.
The intermediate compounds of formulae II, IIIa, IIIb, V, VII, IXa and IXb form a further aspect of the invention.
It will be apparent to those skilled in the art that sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional techniques, for example as described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99 by T W Greene and P G M Wuts, John Wiley and Sons Inc, 1991.
The compounds of the invention are useful because they possess pharmacological activity in animals. In particular, the compounds are useful in the treatment of a number of conditions including hypertension, myocardial infarction, male erectile dysfunction, hyperlipidaemia, cardiac arrhythmia and benign prostatic hyperplasia. The latter condition is of greatest interest. Thus, according to another aspect of the invention, there is provided a method of treatment of benign prostatic hyperplasia which comprises administering a therapeutically effective amount of a compound of the invention to a patient suffering from such a disorder. The use of the compounds of the invention as pharmaceuticals, and the use of the compounds of the invention in the manufacture of a medicament for the treatment of benign prostatic hyperplasia, are also provided.
The compounds of the invention may be administered by any convenient route, for example orally, parenterally (e.g. intravenously, transdermally) or rectally. The daily dose required will of course vary with the particular compound used, the particular condition being treated and with the severity of that condition. However, in general a total daily dose of from about 0.01 to 10 mg/kg of body weight, and preferably about 0.05 to 1 mg/kg, is suitable, administered from 1 to 4 times a day.
The compounds of the invention will generally be administered in the form of a suitable pharmaceutical formulation. Thus, according to another aspect of the invention, there is provided a pharmaceutical formulation including preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. The pharmaceutical formulation is preferably in unit dose form. Such forms include solid dosage forms, for example tablets, pills, capsules, powders, granules, and suppositories for oral, parenteral or rectal administration; and liquid dosage forms, for example sterile parenteral solutions or suspensions, suitably flavoured syrups, flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil and peanut oil, and elixirs and similar pharmaceutical vehicles.
Solid formulations may be prepared by mixing the active ingredient with pharmaceutical carriers, for example conventional tabletting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums and other diluents, for example water, to form a homogeneous preformulation formulation in which the active ingredient is uniformly dispersed so that it may be readily subdivided into equally effective unit dosage forms containing typically from 0.1 to about 500 mg of the active ingredient. The solid dosage forms may be coated or otherwise compounded to prolong the action of the formulation.
The formulations of the invention may also contain a human 5-xcex1 reductase inhibitory compound [see International Patent Application WO 95/28397], or a compound of the invention could be presented in a pharmaceutical pack also containing a human 5-xcex1 reductase inhibitory compound as a combined preparation for simultaneous, separate or sequential use.
The compounds of the invention may be tested in the screens set out below.
Contractile Responses of Human Prostate
Prostatic tissue was cut into longitudinal strips (approximately 3xc3x972xc3x9710 mm) and suspended in organ baths under a resting tension of 1 g in Krebs Ringer bicarbonate of the following composition (mM): NaCl (119), KCl (4.7). CaCl2 (2.5), KH2PO4 (1.2), MgSO4 (1.2), NaHCO3 (25), glucose (11), and gassed with 95% O2/5% CO2. The solution also contained 10 mM cocaine and 10 mM corticosterone. Tissues were exposed to a sensitising dose of (xe2x88x92)-noradrenaline (100 mM) and washed over a 45 minute period. Isometric contractions were obtained in response to cumulative additions of (xe2x88x92)-noradrenaline to obtain control curves in all tissues. A further curve was then generated in the presence or absence of antagonist (incubated for 2 hours). Antagonist affinity estimates (pA2) were determined using a single concentration of competing antagonist, pA2=xe2x88x92log[A]/(DRxe2x88x921) where the dose ratio (DR), relative to corresponding controls, was produced by a single concentration of antagonist [A], assuming competitive antagonism and Schild regression close to unity.
Anaesthetised Dog Model of Prostatic Pressure and Blood Pressure
Mature male beagles (12-15 kg body weight) were anaesthetised with sodium pentobarbitone (30-50 mg/kg i.v.) and a tracheal cannula was inserted. Subsequent anaesthesia was maintained using pentobarbitone infusion. The animals were respirated with air using a Bird Mk8 respirator (Bird Corp., Palm Springs, Calif. USA) adjusted to maintain blood gasses in the range pO2 90-110 mm Hg, pCO2 35-45 mm Hg, pH 7.35-7.45. Body temperature was maintained at 36-37.5xc2x0 C. using a heated operating table. Catheters were placed into the left femoral artery for recording blood pressure and into the left femoral vein for compound administration. Heart rate was recorded via the lead II E.C.G. A laparotomy was performed to cannulate both ureters to prevent chance of fluid volume within the bladder. A 7F cardiac catheter (with a 1.5 ml capacity balloon tip) was inserted into the bladder via the urethra. The balloon was filled with air and the catheter withdrawn until the balloon became lodged in the prostate, which was confirmed by digital pressure. Balloon pressure was recorded via a Druck transducer. Prostatic pressure and haemodynamic parameters were made on a Grass Polygraph (Grass Instruments. Quincy, Mass, U.S.A.) and the data measured on line using a Motorola 68000-based microcomputer system (Motorola Inc., Temple, Ariz., U.S.A.). Compounds were made up in PEG 300 and administered i.v. through a catheter in the femoral vein. Responses to phenylephrine (1-16 xcexcg/kg i.v. in saline) were obtained to generate control dose-response curves (two control curves for each experiment). Compounds were administered (in terms of compound base) at 10-300 xcexcg/kg i.v. 5 min before construction of phenylephrine curves (constructed up to a maximum dose of 128 xcexcg/kg in the presence of test compound).
Due to xcex11-related dysrhythymic properties of phenylephrine, absolute maximal responses were not obtained but were taken as 10% greater than the control response obtained with 16 xcexcg/kg phenylephrine. Drug concentrations were calculated on the basis of molar weight of compound/kg body weight thus allowing a xe2x80x9cpseudo pA2xe2x80x9d calculation by Schild analysis using dose ratios derived from shifts in the phenylephrine dose-response curves.
The compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective (in particular they may have beneficial effects in benign prostatic hyperplasia without causing undesirable cardiovascular effects, for example because they are able to selectively antagonise prostatic receptor subtypes of the xcex11-adrenoceptor), or have other more useful properties than the compounds of the prior art.
The invention is illustrated by the following examples, in which the following abbreviations are used:
DMF=dimethylformamide
DMSO=dimethylsulphoxide
EtOAc=ethyl acetate
EtOH=ethanol
h=hour
MeOH=methanol
min=minute
n-BuOH=n-butanol
THF=tetrahydrofuran
Intermediate 1
1-(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride
(a) 1-(t-Butyloxycarbonyl)-1,4-diazepane
To a solution of homopiperazine (100 g, 1.0 mol) and triethylamine (210 ml, 152 g, 1.5 mol) in CH2Cl2 (500 ml) at 0xc2x0 C. was added a solution of di-(t-butyl) dicarbonate (195 g, 0.89 mol) in CH2Cl2 (300 ml). The mixture was allowed to warm to room temperature and stirred for 18 h after which time the CH2Cl2 was evaporated under reduced pressure. The resulting residue was partitioned between ether and 2N citric acid and the aqueous layer was extracted with ether (4xc3x97200 ml). The aqueous layer was basified with 2N aqueous NaOH and then extracted with CH2Cl2 (4xc3x97400 ml). The combined CH2Cl2 extracts were washed with H2O (2xc3x97), saturated brine (1xc3x97) and dried over MgSO4. Evaporation under reduced pressure followed by azeotroping with CH2Cl2 (4xc3x97) gave the subtitle compound as a yellow waxy solid (94.3 g, 53%). Rf 0.25 (CH2Cl2/MeOH/0.88 NH3 90/10/1, v/v). MS m/z 201 (MH+). Found: C,58.86; H,10.03; N,13.58; C10H20N2O2 0.05.CH2Cl2 requires C,59.02: H, 9.91; N,13.70%.
(b) 1-(t-Butyloxycarbonyl)-4-(4-morpholinecarbonyl)-1,4-diazepane
A solution of the compound of step (a) (92.0 g, 0.46 mol) and triethylamine (96.0 ml, 69.7 g. 0.69 mol) in CH2Cl2 (500 ml) at 0xc2x0 C. was treated dropwise with a solution of 4-morpholinecarbonyl chloride (64.0 ml, 82.0 g, 0.55 mol) in CH2Cl2 (100 ml) and the reaction was stirred at room temperature under N2 for 18 h. The reaction mixture was then diluted with CH2Cl2 (400 ml) and washed with 2N citric acid (3xc3x97400 ml), saturated brine (1xc3x97500 ml), dried over MgSO4 and evaporated to give the subtitle compound as an off-white solid (141.7 g, 98%). Rf 0.80 (CH2Cl2/MeOH/0.88 NH3 90/10/1, v/v). MS m/z 314 (MHxe2x88x92). Found: C,57.50; H,8.69; N,13.41; C15H27N3O4 requires C,57.50; H,8.69; N,13.41%.
(c) 1 -(4-Morpholinecarbonyl)-1,4-diazepane hydrochloride
A solution of the compound of step (b) (140.0 g, 0.44 mol) in CH2Cl2/MeOH (1/1, v/v, 600 ml) at 0xc2x0 C. was saturated with HCl gas and the reaction mixture was stirred at room temperature under N2 for 18 h after which time the reaction mixture was evaporated under reduced pressure and slurried in EtOAc to give, after filtration, a white hygroscopic solid. This was further purified by slurrying in acetone, filtering, washing with ether and drying under reduced pressure at 60xc2x0 C. to give the title compound as a colourless solid (99.0 g, 90%). Rf 0.41 (CH2Cl2/MeOH/0.88 NH3 84/14/2, v/v). MS m/z 214 (MH+). Found: C,47.50; H,8.10; N,16.55; C10H19N3O2 HCl 0.2.H2O requires C,47.41; H,8.12; N,16.59%.
Intermediate 2
1-Acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane
To a solution of Intermediate 1 (50 g, 0.2 mol) and triethylamine (42 ml, 30.5 g, 0.3 mol) in CH2Cl2 (400 ml) at 5xc2x0 C. was added acetic anhydride (23 ml, 24.9 g, 0.24 mol) dropwise over 15 min and the reaction was then stirred for a further 2 h at room temperature under N2. Dilution with CH2Cl2 (600 ml) was followed by washing with saturated aqueous sodium bicarbonate (2xc3x97200 ml) and the combined aqueous layers extracted with CH2Cl2 (1xc3x97100 ml). The CH2Cl2 layers were combined and washed with saturated brine, dried over MgSO4 and evaporated to give a light brown oil. This was dissolved in CH2Cl2 (300 ml) and treated with triethylamine (8 ml, 5.8 g, 0.06 mol) and EtOH (5 ml), stirred for 1 h at room temperature then washed with saturated sodium bicarbonate and the aqueous layer extracted with CH2Cl2 (5xc3x97). The combined CH2Cl2 layers were dried over MgSO4 and evaporated under reduced pressure to give a yellow oil that was then azeotroped with CH2Cl2 (4xc3x97) to give the title compound as a yellow oil (47.1 g, 92%). Rf 0.45 (CH2Cl2/MeOH/0.88 NH3 90/10/1, v/v). MS m/z 256 (MH+). Found: C,52.62; H,8.18; N,15.02; C12H21N3O3 0.3.CH2Cl2 requires C,52.61; H,7.75; N,14.96%.
Intermediate 3
1-(4-Morpholinesulphonyl)-1,4-diazepane hydrochloride
(a) 1-(t-Butyloxycarbonyl)-4-{4-morpholinesulphonyl}-1,4-diazepane
The subtitle compound was prepared by the method of Intermediate 1(b) from the compound of Intermediate 1(a) and 4-morpholinesulphonyl chloride [Repine et al, J. Med. Chem., 34, 1935 (1991)]. The reaction mixture was partitioned between CH2Cl2 and 1N NaOH. The organic phase was washed with 1N HCl, then H2O and dried over MgSO4 and evaporated under reduced pressure. Purification on silica gel eluting with CH2Cl2/MeOH/0.88 NH3 (98/1.25/0.25, v/v) initially and then (96/3.5.0.5, v/v) gave the subtitle compound as a gum (53%). Rf 0.44 (CH2Cl2/MeOH/0.88 NH3 96/3.5/0.5, v/v). MS m/z 350 (MH+). 1H NMR (CDCl3) xcex4: 1.4 (9H, s), 1.9 (2H, m), 3.17 (4H, m), 3.22 (2H, m), 3.4 (2H, m), 3.5 (2H, m), 3.73 (6H, m).
(b) 1-(4-Morpholinesulphonyl)-1,4-diazepane hydrochloride
The title compound was prepared by the method of Intermediate 1(c) from the product of step (a) above. The subtitle compound (97%) was obtained as a white solid. Rf 0.09 (CH2Cl2/MeOH/0.88 NH3 92/7/1, v/v). MS m/z 250 (MH+). 1H NMR (d6-DMSO) xcex4: 2.1 (2H, m), 3.1 (4H, m), 3.4 (4H, m), 3.62 (8H, m), 9.2 (2H, b).
Intermediate 4
2-Acetyl-5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline
(a) 5-Methanesulfonamidoisoquinoline
Methanesulfonyl chloride (3.2 ml, 42 mmol) was added to a solution of 5-aminoisoquinoline (5.0 g, 35 mmol) in pyridine (40 ml) and the mixture was allowed to stand for 72 h. The reaction mixture was then poured into aqueous citric acid (10%, 400 ml) and extracted with EtOAc (2xc3x97230 ml). The organic layer was evaporated to give a residue that was purified on silica gel, eluting with CH2Cl2/MeOH, to afford the subtitle compound as a solid (3.55 g, 46%). Rf 0.03 (CH2Cl2/ether 4/1, v/v). 1H NMR (D6-DMSO) xcex4: 3.07 (3H, s), 7.68 (1H, t), 7.75 (1H, d), 8.03 (1H, d), 8.10 (1H, d), 8.54 (1H, d), 9.32 (1H, s), 9.79 (1H, bs).
(b) 5-Methanesulfonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride
A solution of the product of step (a) (3.50 g, 15.7 mmol) in EtOH (250 ml) was treated with platinum dioxide (1.5 g) and 1N HCl (15.7 ml). The mixture was hydrogenated at a pressure of 414 kPa (60 psi) for 16 h, after which time the reaction mixture was filtered. The filtrate was evaporated under reduced pressure and triturated with CH2Cl2 to afford the subtitle compound as a colourless solid. The solid residue from the filtration was taken up into MeOH/H2O (1:2 v/v), and the suspension filtered, washing with CH2Cl2 (3xc3x97). This filtrate was evaporated to afford a second crop of the subtitle compound (total yield 3.45 g, 84%). Rf 0.21 (CH2Cl2/MeOH/0.88 NH3 90/10/1, v/v). 1H NMR (D6-DMSO) xcex4: 2.96-3.10 (2H, m). 3.31 (3H, m), 4.21 (2H, s), 7.12 (1H, m), 7.26 (2H, m), 9.24 (1H, s), 9.61 (2H, bs).
(c) 2-Acetyl-5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline
To a solution of the product of step (b) (2.87 g, 10.9 mmol) in CH2Cl2 at 0xc2x0 C. was added acetic anhydride (1.2 ml, 13.1 mmol) and triethylamine (3.4 ml, 24.0 mmol), and the reaction was stirred at room temperature for 16 h. The reaction mixture was then partitioned between EtOAc and aqueous sodium bicarbonate solution and the aqueous phase extracted with further portions of EtOAc. The combined organic extracts were dried over MgSO4 and evaporated to afford an oil. This was dissolved in MeOH (15 ml) and treated with aqueous sodium carbonate solution (7%, w/w, 15 ml) and the mixture stirred for 16 h at room temperature, after which time the MeOH was removed under reduced pressure, the pH was adjusted to pH 8 with 2N HCl and the product was extracted with EtOAc (2xc3x97). The combined organic extracts were dried over MgSO4 and evaporated to give an oil that was purified on silica gel, eluting with CH2Cl2/MeOH (95/5, v/v) to give the title compound as an oil (2.0 g, 68%). Rf 0.20 (CH2Cl2/MeOH 9/5, v/v). MS m/z 269 (MH+).